The disease state referred to as glaucoma is characterized by a permanent loss of visual function due to irreversible damage to the optic nerve. The several morphologically or functionally distinct types of glaucoma are typically characterized by elevated intraocular pressure (IOP), which is considered to be causally related to the pathological course of the disease. Ocular hypertension is a condition wherein intraocular pressure is elevated but no apparent loss of visual function has occurred; such patients are considered to be a high risk for the eventual development of visual loss associated with glaucoma. If glaucoma or ocular hypertension is detected early and treated promptly with medications which effectively reduce elevated intraocular pressure, loss of visual function or its progressive deterioration can generally be ameliorated. Drug therapies which have proven to be effective for the reduction of intraocular pressure include both agents which decrease aqueous humor production and agents which increase the outflow facility. Such therapies are in general administered by one of two possible routes, topically (direct application to the eye) or orally.
One class of orally administered drugs which has been used for approximately thirty years to assist in the maintenance of intraocular pressure is carbonic anhydrase inhibitors. These agents inhibit the enzyme carbonic anhydrase, which is present in the ciliary process of the eye and intimately involved in the production of aqueous humor. Drugs of this class act through their ability to decrease the production of aqueous humor. Though these agents are efficacious and nontoxic to ocular tissues following oral administration, they are known to lead to detrimental, systemic (extraocular) side effects. The most serious, but rare, side effects are life-threatening blood dyscrasia and the formation of renal calculi. The more common side effects are nausea, dyspepsia, fatigue, impotence, depression, metabolic acidosis, and others which, although not generally life threatening, are sufficiently debilitating that patients frequently choose to discontinue therapy.
There is, therefore, a clear need for an inhibitor of carbonic anhydrase which would be topically effective, thereby eliminating, or significantly reducing, the detrimental side effects associated with oral administration. The compounds of the present invention are new sulfonamides which are carbonic anhydrase inhibitors useful for lowering IOP without producing significant systemic side effects when delivered topically to the eye.
Compounds of commonly assigned U.S. Pat. No. 5,240,923 possess a chiral center within the 3,4-dihydro-2H-thieno[3,2-e]-1,2-thiazine ring. It has been demonstrated that, in general, one of the two possible stereochemical representations about this center is more active in binding to the target enzyme, carbonic anhydrase. Therefore, for those compounds it is most advantageous to obtain the preferred enantiomer in optically pure form. This can be accomplished by procedures known in the art, such as resolution or synthesis; however, obtaining an optically pure compound can be laborious. Therefore, it is advantageous to employ compounds with no chiral centers, or with as few chiral centers as possible if such alternatives are available. Surprisingly, it was discovered that compounds of the present invention, which do not possess a chiral center within the heterocycle, 2H-thieno[3,2-e]-1,2-thiazine, are in general more potent inhibitors of carbonic anhydrase than the corresponding reduced compounds.
The class of non-steroidal antiinflammatory agents generally referred to as oxicams (e.g. piroxicam) can be considered to be structurally related to the compounds of present interest. Specifically, the compound known as tenoxicam and its numerous substituent variations are similar in that they share a common parent heterocyclic ring structure with the compounds of interest in the present invention: 2H-thieno[2,3-e]-1,2-thiazine. However, there have been no disclosures wherein a sulfamoyl (SO.sub.2 NH.sub.2) group has been contemplated as a substituent within this group of compounds. A primary sulfamoyl group is a required substitution in the context of the present invention. Replacement of the fused benzene ring of piroxicam with a thiophene and further structural variations are disclosed in German Patent No. 2,537,070 and Swiss Patent No. 617,705 (and their related U.S. Pat. Nos. 4,230,873; 4,224,445 and 4,177,193); and European Patent No. 103,142 and U.S. Pat. Nos. 4,180,662 and 4,187,303.
U.S. Pat. No. 5,093,332 discloses 2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-sulfonamide 4,4-dioxides, which are shown to be weak inhibitors of carbonic anhydrase, for treating elevated intraocular pressure and glaucoma. U.S. Pat. Nos. 4,619,939 and 4,746,745 disclose sulfonamides and a process for reducing intraocular pressure by applying topically to the cornea a carbonic anhydrase inhibitor having a particular set of properties. The compounds of this invention are not disclosed in these patents.